Polymeric microparticles have been used for drug delivery for decades. Numerous methods to increase the amount of drug which can be delivered, and to manipulate rate of release, and release profile, have been described. Methods have included altering microparticles size, shape, polymer composition, inclusion of additives such as surfactants and pore forming agents, and inclusion of ligands and bioadhesive agents.
Glaucoma is an ophthalmic disease characterized by the gradual degeneration of retinal ganglion cells (RGCs). RGCs synapse with bipolar cells and transmit visual inputs to the brain along the optic nerve. Degeneration of these cells leads to gradual vision loss and ultimately blindness if untreated. Glaucoma is the second leading cause of blindness (Biomdahl et al., Acta. Opth. Scan., 75, 310-319 (1997)). Glaucoma will affect approximately 60.5 million people in 2010, increasing to 796 million people in 2020 (Quigley et al., Brit. J. Opth., 90, 262-267 (2006)). This includes peoples suffering from both open angle (OAG) and angle closure glaucoma (ACG).
Although a normal tension variant does exist, the development of glaucoma is most often associated with elevated intraocular pressure (IOP) (Migdal et al., Opthmal., 101, 1651-1656 (1994)). This elevated pressure is caused by an excess accumulation of aqueous humor in the eye due to blockage of the trabecular network (Alward et al., Amer. J. Opthmal., 126, 498-505 (1998)). With a majority of glaucoma cases associated with elevated IOP, reduction of this pressure has been found to greatly mitigate degeneration in approximately 90% of the cases, including cases in which IOP is in the normal range but optic neuropathy occurs (Id).
Timolol maleate, a β-adrenergic receptor antagonist, induces an average IOP reduction of 20-35% when administered topically as a solution. Since its approval for ophthalmic applications in 1979, timolol maleate has become the FDA's gold standard for IOP reduction. Eye drops are currently the primary means of delivery for this drug. However, with less than 1% of the topically administered drug reaching the aqueous humor, large numbers of doses daily are required for IOP management. Compliance with this treatment regime is poor with more than half of patients unable to maintain consistently lowered IOP through drops (Rotchford and Murphy, Brit. J. Opthmal., 12, 234-236 (1998)).
Drops also lead to extensive systemic absorption of the administered drug (˜80%, Marquis and Whitson, Drugs & Aging, 22, 1-21 (2005)). This systemic absorption can result in adverse cardiopulmonary side effects (Schuman, Clin. Ther., 22, 167-208 (2000)). Together, these complications make topical application of timolol maleate problematic, especially in the aging population that exhibits the lowest compliance and highest degree of complications (Marquis and Whitson, Drugs & Aging, 22, 1-21 (2005)). There exists a need for a sustained release timolol maleate formulation, which overcomes the limitations of currently available eye drops.
A variety of approaches for the sustained delivery of timolol maleate have been investigated, including the commercially available once daily gel-forming solutions (e.g., 0.5% Timoptic-XE® and Nyogel®), poly(D,L-lactice-co-glycolic acid) (PLGA) films, chitosan treated alginate beads, and soft contact lenses containing N,N-diethylacrylamide and methacrylic acid. None of the formulations, however, result in sustained release of timolol maleate for longer than 14 days, far short of the 90 day minimum delivery required to fundamentally alter the treatment of glaucoma. For example, Nyogel® (0.01% timolol hydrogel formulation) provides similar efficacy to 0.5% timolol aqueous solution eye drops with some reduction in side effects, but only lasts for 24 hours. PLGA films incorporating timolol maleate were studied, but release of the drug on the corneas of ocularly hypertensive rabbits was achieved for only five days. Further, few of these formulations are conducive to subconjunctival injection, a minimally invasive procedure well tolerated by patients, as they are formulated as contact lenses or plugs or films which are implanted on the eye. Such implants can be irritating to the eye and/or can fall out.
U.S. Pat. No. 6,726,918 to Wong describes methods for treating inflammation-mediated conditions of the eye, the methods including implanting into the vitreous of the eye a bioerodible implant containing a steroidal anti-inflammatory and a bioerodible polymer, wherein the implant delivers an agent to the vitreous in amount sufficient to reach a concentration equivalent to at least about 0.65 μg/ml dexamethasone within about 48 hours and maintains a concentration equivalent to at least about 0.03 μg/ml dexamethasone for at least about three weeks. Wong does not disclose administering the implants by subconjunctive injection.
U.S. Patent Application Publication No. 2006/0173060 to Chang et al. describes biocompatible microparticles containing an alpha-2-adrenergic receptor agonist and a biodegradable polymer. The microparticles can allegedly be used to treat glaucoma. Chang alleges that the microparticles release the active agent for a period of time of at least about one week, such as between two and six months. Chang discloses that the microparticles can be administered subconjunctivally.
U.S. Patent Application Publication No. 2004/0234611 to Ahlheim et al. describes an ophthalmic depot formulation containing an active agent embedded in a pharmacologically acceptable biocompatible polymer or a lipid encapsulating agent for periocular or subconjunctival administration. The formulation can be in the form of microparticles or nanoparticles. Ahlheim discloses that the depot formulations are adapted to release all or substantially all of the active material over an extended period of time (e.g., several weeks up to 6 months). Suitable active agents are listed in paragraphs 0033 to 0051 and include timolol maleate; however, the preferred active agent is a staurosporine, a phthalazine, or a pharmaceutically salt thereof. Suitable polymers are listed in paragraphs 0014 to 0026. Ahlheim does not show in vivo release of an effective amount of timolol maleate over a period of greater than 14 days. In fact, Ahlheim contains no examples showing in vitro or in vivo release of any active agents, let alone timolol maleate.
Aggarwal describes chitosan or Carbopol coated niosomal timolol maleate formulations prepared by reverse phase evaporation (REV) (Aggarwal et al., int. J. Pharm., Vol. 290 (1-2), 155-159 (2003)). The coated timolol maleate formulation was compared to timolol solution in term of in vitro release and IOP lowering pharmacodynamic effect. The coated timolol maleate formulations released 40-43% of the drug after 10 hours and showed a more sustained effect on IOP for up to eight hours. Aggarwal does not disclose or suggest release of an effective amount of timolol maleate over an extended period of time, for example, greater than 14 days.
None of the references discussed above optimizing the charge, hydrophilicity, an/or the molecular weight of the polymers used prepare microparticles in order to maximize drug loading and release of an effective amount of the drug for a desired period of time.
Therefore, it is an object of the invention to provide sustained release polymeric microparticulate compositions which have been optimized to maximize drug loading and release an effective amount of a drug (or drugs) for a desired period of time.
It is a further object of the present invention to provide such formulations useful for reducing intraocular pressure (IOP) which provide sustained release of an amount of drug comparable to that administered topically for more than 14 days in vivo, and methods of making and using thereof.
It is further an object of the invention to provide sustained release compositions of one or more active agents useful for reducing intraocular pressure (IOP) which provide sustained release for more than 14 days in vivo, and methods using thereof, wherein the compositions exhibit minimal adverse side effects and is well tolerated by patients.